Mental retardation due to maternal phenylketonuria (PKU) is an impending social and economic problem. Consequently, this investigation will focus entirely on the brain dysfunction resulting from fetal brain damage. Biochemical and behavioral indices of fetal cerebrum development in a normal and a phenylketonuric-like environment will be examined. A simulation of PKU will be induced in pregnant rats by continuous subcutaneous infusion of either p-chlorophenylalanine in combination with phenylalanine or phenylacetate, a neurotoxic metabolite produced in excessive amounts in clinical PKU. The cerebrum of the progeny will be analyzed for DNA, protein, cholesterol, and gangliosides. Whether the availability of acetyl-CoA is a critical factor for the biosynthesis of gangliosides in the rapidly developing brain will be investigated. The density of acetylcholine and GABA receptor sites in the mature cerebrum and hippocampus will be compared. Behavioral tests are selected to determine whether any of the biochemical abnormalities resulting from the simulated maternal PKU are associated with a delay in functional development (reflexes, preweaning, learning), deficits in cognitive functions (spatial and memory) and changes in non-cognitive behaviors (behavioral arousal and response inhibition). Information gathered from this investigation should contribute to our understanding of the normal development of acetylcholine and GABA synapses and the acquisition of normal behavior. Results may reveal causal relationships of ganglioside content and pattern during very early synaptic development to density of cholinergic and GABAergic receptors and in turn to behavior in the young as well as the mature animal. Data accumulated will aid in devising an improved treatment for maternal PKU and in the selection of suitable parameters (biochemical and behavioral) for the assessment of its effectiveness.